Role of placenta growth factor and its receptor flt-1 in rheumatoid inflammation: a link between angiogenesis and inflammation

Arthritis Rheum. 2009 Feb;60(2):345-54. doi: 10.1002/art.24289.


Objective: To investigate the direct effects of placenta growth factor (PlGF) and its specific receptor, flt-1, which are known to mediate angiogenesis, on the inflammatory process of rheumatoid arthritis (RA).

Methods: Expression of PlGF and flt-1 in the synovial tissue of RA patients was examined using immunohistochemistry. Enzyme-linked immunosorbent assay was used to determine the concentrations of PlGF, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) in culture supernatants of either mononuclear cells or synoviocytes. The flt-1 expression level in mononuclear cells was analyzed by flow cytometry. Experimental arthritis was induced in mice either by immunization with type II collagen (CII) or by injection of anti-CII antibody.

Results: PlGF was highly expressed in the synovium of RA patients, and its primary source was fibroblast-like synoviocytes (FLS). When stimulated with IL-1beta, FLS from RA patients produced higher amounts of PlGF than did FLS from patients with osteoarthritis. Exogenous PlGF specifically increased the production of TNFalpha and IL-6 in mononuclear cells from RA patients (but not those from healthy controls) via a calcineurin-dependent pathway. The response to PlGF was associated with increased expression of flt-1 on RA monocytes, which could be induced by IL-1beta and TNFalpha. A novel anti-flt-1 hexapeptide, GNQWFI, abrogated the PlGF-induced increase in TNFalpha and IL-6 production, and also suppressed CII-induced arthritis and serum IL-6 concentrations in mice. Moreover, genetic ablation of PlGF prevented the development of anti-CII antibody-induced arthritis in mice.

Conclusion: Our data suggest that enhanced expression of PlGF and flt-1 may contribute to rheumatoid inflammation by triggering production of proinflammatory cytokines. The use of the novel anti-flt-1 peptide, GNQWFI, may be an effective strategy for the treatment of RA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / metabolism*
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Arthritis, Rheumatoid / physiopathology
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gene Silencing
  • Humans
  • Inflammation / metabolism*
  • Interleukin-1beta / pharmacology
  • Interleukin-6 / metabolism
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Middle Aged
  • Neovascularization, Pathologic / metabolism*
  • Oligopeptides / pharmacology
  • Osteoarthritis / metabolism
  • Osteoarthritis / pathology
  • Placenta Growth Factor
  • Pregnancy Proteins / genetics
  • Pregnancy Proteins / metabolism*
  • Pregnancy Proteins / pharmacology
  • Synovial Membrane / pathology
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism*


  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • Oligopeptides
  • PGF protein, human
  • Pgf protein, mouse
  • Pregnancy Proteins
  • Tumor Necrosis Factor-alpha
  • Placenta Growth Factor
  • FLT1 protein, human
  • Vascular Endothelial Growth Factor Receptor-1